This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous studies from our group demonstrated that depletion of CD8-positive T lymphocytes in macaques vaccinated with SIVmac239delta3 resulted in partial abrogation of protection against intravenous challenge with SIVmac251. However, interpretation of these results is in part complicated by the incomplete protection induced by this more attenuated strain of SIV against IV challenge as compared with less attenuated strains such as SIVmac239deltanef. Based on our results demonstrating sterile protection against vaginal challenge with SIVmac251 in animals vaccinated with SIVmac239delta3, we examined the effect of CD8-positive lymphocyte depletion in animals vaccinated with delta3 and then vaginally challenged with SIVmac251. Macaques infected with SIVdelta3 developed relatively strong SIV-specific cellular immune responses that exhibited a transitional effector memory cell phenotype and were maintained for periods of up to 52 weeks after infection. Following vaginal challenge with SIVmac251, infection was observed in 2/4 CD8 depleted delta3-vaccinated animals and 1/4 delta3-vaccinated animals that received control antibody. Interestingly, depletion of CD8-positive T cells resulted in reactivation of SIVdelta3 even in the absence of detectable SIVmac251 infection. While these data do not provide definitive evidence for the role of CD8 cells in mediating resistance against vaginal challenge, they do demonstrate that SIVdelta3 persists for extended periods in infected animals and is held in check by CD8-positive lymphocytes.